New methods in one-electron 18F-fluorination and fluoroalkylation

Thesis

Chapter 1 provides an overview of key concepts in 18F-radiochemistry, including the principles of positron emission tomography (PET), a comparison of commonly used PET radionuclides, and the production and handling of [18F]fluoride. An account of the developments in strategies for one-electron 18F-radiofluorination and 18F-radiofluoroalkylation is then given. Lastly, the aims of this thesis are presented.

Chapter 2 introduces the physical properties of 2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) and TEMPO-derived alkoxyamines. Previous work on the photoredox functionalisation of TEMPO-derived alkoxyamines as well as studies on their cleavage mechanism are then discussed. Finally, the development and applications of a novel photoredox process for the 19F- and 18F-fluorination of TEMPO-derived alkoxyamines are described.

Chapter 3 introduces the properties of the fluoromethyl (CH2F) group and fluoromethyl radical, followed by an account of strategies for the fluoromethylation of alkenes. Next, a silyl radical-mediated process for the hydro(radio)fluoromethylation of electron-deficient alkenes with fluoroiodomethane is presented, followed by an extension of this activation strategy to other halomethyl synthons. Building on these results, the development and applications of a protocol for the hydromethylation of electron-deficient alkenes with iodomethane are then discussed. Lastly, a novel metallophotoredox process for the 19F-fluoromethylation of aryl bromides with fluoroiodomethane is disclosed, along with initial efforts towards the translation of this methodology to the 18F-fluoromethylation of aryl halides.

Chapter 4 introduces the properties of the geminal difluoromethyl(ene) motif and provides an overview of the progress made to date in the synthesis of 18F-difluoromethyl(ene) compounds. The application of a manganese-mediated 18F-fluorodecarboxylative strategy to the synthesis of 18F-difluoromethyl(ene) compounds is then described, with a focus on scale-up and automation for postlabelling diversification reactions.

Chapter 5 contains the experimental details and procedures for the work disclosed in Chapters 2–4 of this thesis.

Authors: Ortalli, S

• DOI: 10.5287/ora-kzw2985po
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: fluorine-18; fluorination; fluoroalkylation
• Subjects: Radiochemistry; Organic chemistry; Fluorine chemistry